Diazinyl carboxy-alkyl sulphides and salts thereof



Patented May 2, 1944 DIAZmYL CARBOXY-ALKYL SULPHIDES AND SALTS THEREOF Gaetano F. DAlelio and James W. Underwood, Pittsfield, Mass., assignors to General Electric Company, a corporation of New York No Drawing. Application December 18, 1941, Serial No. 423,564

16 Claims.

This invention relates to new chemical compounds and more particularly to diazine derivatives. The invention especially is concerned with the production of new and useful diazinyl carboxy-alkyl sulphides and salts thereof.

The chemical compounds of this invention may be represented by the following general formula:

In the above formula n represents an integer and is at least 1 and not more than 2, R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and substituted hydrocarbon radicals, more particularly halo-hydrocarbon radicals, and Z represents a member of the class consisting of hydrogen and elements and radicals that can be substituted for the hydrogen atom of a COOH grouping, more particularly the alkali metals (sodium, potassium, lithium, caesium and rubidium) and the ammonium (NH4) radical. Thus, when Z stands for hydrogen the diazinyl carboxy-alkyl sulphides of this invention may be represented by the formula where n and R have the meanings above given with reference to Formula I. When Z in Formula I is other than hydrogen, the compounds of the invention may be represented by the formula III where M represents a member of the class consisting of elements and radicals that can be substituted for the hydrogen atom of a -COOH grouping, specifically the ammonium radical or an alkalimetal, and n and R have the meanings above given with reference to Formula I.

I From a consideration of the above formulas it .willbe seen that, since 11, represents an integer which is 1 or 2, the linkage of the (C1LR2) COOZ grouping (Formula I) to the sulphur atom in all cases will be alpha or beta to the -COOZ group- I ing. It also will be observed that linkage of the diazinyl grouping to the sulphur atom is through a carbon atom.

Illustrative examples of radicals that R in the above formulas may represent are: aliphatic ,(e. g., methyl, ethyl, propyL'isopropyl, allyl', butyl,

secondary butyl, isobutyl, butenyl, amyl, methallyl, ethallyl, tertiarybutyl, crotyl, heptyl, isoheptyl, octyl, decyl, isoamyl, hexyl, etc.); including cycloaliphatic (e. g., cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, etc.) aryl (e. g., phenyl, diphenyl or xenyl, naphthyl, etc.); aliphatic-substituted aryl (e. g., tolyl, xylyl, ethylphenyl, propylphenyl, isopropylphenyl, allylphenyl, 2-butenylphenyl,' tertiary-butylphenyl, etc.); aryl-substituted aliphatic (e. g., benzyl, phenylethyl, phenylisopropyl, cinnamyl, etc.); and their homologues, as well as those groups with one or more of their hydrogen atoms substituted by, for example, a halogen. Specific examples of halogeno-substituted hydrocarbon radicals are chloromethyl, chloroethyl, chlorophenyl, dichlorophenyl, chlorocyclohexyl, ethyl chlorophenyl, phenyl chloroethyl, bromoethyl, bromopropyl, bromotolyl, etc. Preferably R in Formulas I, II and III is hydrogen. However, there also may be produced in accordance with the present invention chemical compounds such, for instance, as those represented by the general formulas:

and, more particularly,

R-C/ M-r -SCHOOOH where n and B have the same meanings as given above with reference to Formula I.

The new compounds of this invention may be used as chemotherapeutic agents and as intermediates in the preparation of derivatives thereof such as ureido, hydrazino, acyl, carbamyl, amidine, etc., derivatives of the individual compound embraced by Formula I. Compounds containing a COOI-I grouping may be esterified or amidated; or the hydrogen of the carboxy grouping may be replaced by a substituent such, for instance, as an ammonium radical or a monovalent metal, e. g.,. an alkali metal such as sodium, potassium, lithium, etc, thereby to obtain compounds such as represented by Formula III.

,. be condensed with, for'instanca'aldehydes', in-

cluding polymeric aldehydes and aldehyde-addition products, to yield condensation products of particular utility in the plastics and coating arts. Our new compounds containing a COOH grouping are especially useful When intercondensed with amidogen-aldehyde (e. g., urea-formaldehyde, melamine-formaldehyde, etc.) partial condensation products to effect or to accelerate the a conversion of such partial condensation products from a soluble, fusible state to a cured or insoluble and infusible state. Condensation products of these new organic sulphides with aldehydes are more fully described and are specifically claimed in our copending application Serial No. 432,894, filed February 28, 1942, and assigned to the same assignee as the present invention.

Various methods may be employed to J produce the chemical compounds of this invention.- We prefer to prepare them by effecting reaction, in the presence of a hydrohalide acceptor, between a diamino [(NHR)2] mercapto pyrimidine and a halo-alkyl monobasic acid or a- Water-soluble salt of such an acid, e. g., an ammonium salt or analkali-metal salt; We prefer to use, an alkali-metal salt, for instance-the sodium'or potassium salt, of a halo-alkyl monobasic acid. When a salt or the. acid is used, thereis first produced a salt (for example, an ammonium or an alkali-metal salt depending'upon the: particular starting reactant) of the diamino pyrimidyl carboxy-alkyl sulphide. The carboxy derivative is obtained by treating this salt with hydrochloric, hydrobromic, sulphuric Or other suitable organic or inorganic acid in an amount just sufficient to decompose the salt and to convert the COOM grouping of the pyrimidine derivative to a COOH grouping.

Illustrative examples of mercapto pyrimidines that may be used, depending upon the particular end-product desired, are:

-butyl 4 mercapto Z-naphthylamino S-butylphenylamino 5-naphthyl pyrimidine i-mercapto 2-cyclohexylamino G-methylamino 5- chloronaphthyl pyrimidine e-mercapto 2,6-diamino pyrimidine 4-mercapto 2,6-di-(methylamino) pyrimidine l-mercapto 2,6-di-(anilino) pyrimidine 4-mercapto 2,6-di-(chlo1oanilin0) pyrimidine 2- mercapto 4,6-di- (chlorobutylamino) pyrimidine t 2-mercapto 4,6-di-(bromonaphthylamino) rimidine 2-mercapto it-amino S-ethylamino pyrimidine Z-mercapto 4,6-di-(propylamino) pyrimidine Z-mercapto 4-allylamino B-butylamino pyrimidine 2-mercapto. 4-butylamino G-cyclopentylamino pyrimidine 2-mercapto 4-(3-butenylamino) S-propylamino 5-methy1 pyrimidine Z-mercapto 4-pentylamino G-cyclohexylamino pyrimidine d-mercapto Z-aminoanilino 6-ethylphenylamino 5-chlorophenyl pyrimidine v l-mercapto 2-cycloheptylamino G-propylphenylamino 5-methyl pyrimidine 2-mercapto l-isopropylanilino G-phenylpropylamino pyrimidine Z-mercapto 4-dichloroanilino 6-chloroethylamino pyrimidine 2-mercapto 4-i0d0anilino G-methylamino pyrimidine Z-mercapto 4-amino B-methylamino pyrimidine Z-mercapto bamino 6benzylamino pyrimidine 2-mercapto 4-amino 6-bromoethylamino pyrimidine Z-mercapto e-cyclohexenylamino G-naphthylamino pyrimidine 2-mercapto -bromotoluido 6-benzylamino. 5-

chlorophenyl pyrimidine Z-mercapto 4,6-diamino 5-methyl pyrimidine Z-mercapto 4,6-diamino 5-phenyl pyrimidine e-mercapto 2,6-diamino 5-chlorobutyl pyrimidine Z-mercapto 4,6-diamino fi-cyclohexyl pyrimidine 2-mercapto 4,6-diamino 5-naphthy1 pyrimidine 2-mercapto 4,6-di-(cyclohexylamino) pyrimidine Illustrative examples of halo-alkyl monobasic acids and water-soluble salts-of halo-'alkyl monobasic acids that may be employed, depending upon the particular end-product desired, are:

chloroacetic acid Alpha-chloropropionic acid Beta-chloropropionic acid 'Alpha-bromopropionic acid Beta-bromopropiorfic acidv Alpha-iodopropionic acid Beta-iodopropionic acid Alpha-phlorobutyric acid Beta-chlorobu-tyric acid Alpha-chloroisobutyric acid Beta-chloroisobutyric. acid Alpha-bromobutyric acid Phenyl chloroacetic acid Bromoacetic acid Iodoacetic acid Alpha-chloro pentanoic acid Beta-chloropentanoic acid Beta-"iodo pentanoic' acid.

'Alpha-tolylbeta-phenyl b'eta-chlorobutyric acid Alpha-benzyl alpha-cyclopentyl beta, beta-dinaphthyl beta-iodo propionic acid Alpha-naphthyl beta-chlorophenyl beta-bromo butyric acid Alpha-methyl alpha-chloro propionic acid Alpha: alpha, beta-trimethyl beta-bromo butyric aci Alpha-.phenyl alpha-iodo butyric acid Tolyl chloroacetic acid 7 Xylyl bromoacetic acid a l and the alkali-metal and: ammoniummsalts :oi

halo-alkyl mo-nobasic acids: such asx'above mentioned by way of illustration, for example the sodium, potassium, lithium; etc., salts of such halo-alkyl monobasic acids... Various hydrohalide acceptors may be em- ,ployed. We prefer to use a-hydrohalide' acceptor that will react with the mercapto pyrimidine to form a water-soluble salt. Examples of such acceptors are the alkali-metal hydroxidesge': 'g.,

sodium hydroxide, potassium hydroxide; etc.

Additional examples, of; hydrohalide. acceptors thatmay be used -are other inorganic" bases,

e."g'., calcium hydroxide, barium hydroxide, am monium hydroxide, etc.; carbonates of inorganic bases,'including the carbonates of alkali metals; organic amines such as tertiary amines, e; g., trimethyl amine, triethyl amine, 'tributylamine', pyridine, dimethyl aniline, quinoline'g. etc.; quaternary ammonium bases, e. g., tetram'ethyl ammonium hydroxide, etc.; and the like.

The rea'cticnbetween the mercaptoidiamino pyrimidine and the haloi-alkyl monobasic .acid (or; water-soluble salt thereof) 'may be carried out in any suitable manner, but preferably is effectedin the presence of a suitable solvent or mixture of solvents. Although various solvents and solvent mixtures may be employed, for economic reasons and because of their eminent suitability we prefer to use wateror a mixture oi water and alcohol. The reactionmay be carried out under a variety of temperature and pressure conditions, for instance at. normal or at elevated temperatures. and at atmospheric, sub-atmospheric or super-atmospheric pressures. When :the starting reactant is a halo-alkyl r'nonobasic acid, the reaction may be represented by the following general equation:

In the above equation X represents halogen, and n and R have the same meanings as given above with reference to Formula I.-

When a water-soluble salt, specifically an ammonium salt or an alkali-metal salt, of a haloalkyl monobasic acid is used as a starting reactant in the preparation of a diamino pyrimidyl carboxy-alkyl sulphide, the following equations illustrate the reaction:

In the above equations (VII-A and VII-B) HA represents an acid capable of converting the -.-.PM er i e i. th s mr u d ea d .wa

-COOH grouping, specifically an inorganic acid (e. g., hydrochloric, hydrobromic, sulphuric, etc.) n and R have the meanings given abovewith referenceto FormulaI, and M has the meaning given above with reference to Formula III. MA represents the salt of the acid represented by HA.

The new chemical compounds of this invention also may be prepared by efiecting reaction between a halogenated diamino pyrimidine (that is, a diamino pyrimidine having a halogen atom attached directly to acarbon atom of the pyrimidine nucleus) and a mercapto-alkyl monobasic acid (or a suitable salt thereof, e. g., the alkalimetal salt thereof) in the presence of a hydro! halide acceptor. This reaction may be carried out by any suitable means but, preferably is efiected in the presence of an anhydrous solvent. The other conditions of reaction may be the same as described above with reference to the firstmentioned method of preparation.

In order that those skilled in the art better may understand how the present invention may be carried into efiect, the following illustrative examples are given. All parts are by'weight.

Example 1;

The stated amounts of 2-mercapto 4,6-diamino pyrimidinev and sodium hydroxide were dissolved in the stated amount of water. The sodium chloroacetate was now added and the resulting mixture was heated under reflux at the boiling temperature of the mass for minutes, after which the mass was allowed tostand at room temperature for about 16 hours. In this way there was formed in solution the sodium salt of 4,6-diamino pyrimidyl-2 carboxy-methyl sulphide. An acid, specifically hydrochloric acid, was added to the solution in an amount just sufficientlto make. it faintly acid to litmus. A crystalline precipitate comprising 4,6-diamino pyrimidyl-2 carboxy-methyl sulphide separated from the acidifiedsolution. This precipitate was filtered off, washed freeof soluble impurities such as the chlorides, and then dried.

Example 2 2,6-diamino pyrimidyl-4 carbjoxy-methyl sulphide, which also may be named 2,4-diamino pyrimidyl-6 carboxy-methyl sulphide,is prepared in essentially the same manner as described under Example 1 with the exception-that 100 parts of 4-mercapto 2,6-diamino pyrimidine is used as a starting reactant instead of 100 parts of 2'-mercapto 4,6 -d iamino pyrimidine.

Example 3 7 Erample 4 v 4,6-diamin0 py imidyl-2 alphacarboxy-ethyl) sulphide is prepared in essentially the same chloroacetate. v

Other examples of the chemical compounds of thisrinvention are listed below:

d-amino fi-methylainino pyrimidyl-2 methyl sulphide 2-amino 6-ethylamino pyrimidyl-4 methyl sulphide V 4,6-diamino -methyl methyl sulphide V i 7 2,6-diamino S-methyl pyrimidyl-4 carboxymethyl sulphide carboXycarboxypyrimidyl-2 carboxy- 2,6-diamino pyrimidyl-d alpha-(carboXy-ethyl) su c i c 2,6-diamino pyrimidyl-4 beta-(carboxy-ethyl) sulphide 4-,6-di- (methylamino) boxy-ethyl) sulphide 4,6-di- (ethylamino'l pyrimidyl-Z carboxy-methyl sulphide 4,6-di-(anilino') pyrimidyl-2"carboxy methyl sulphide; t V 4,6-di-(anilino) 5-methylv pyrimidyl z .alpha- (carboxy-ethyl) sulphide V V 4-ethylamino 6-anilino 5-butyl. .pyrimidyl-2- alphaalphasmethyl .carboxyethyl) sulphide 4,,6-di- (chloroanilino) pyrimidyl -.'2. carboxy- 7 .methyl sulphide i c 4,6-di-(cyclohexylamino) pyrimidy1-2 alpha- (carboxy-ethyl') sulphide 4,6-di-(methy1aminol pyrimidyl-2: alpha-(carboxy-propyl). sulphide 4-propy1amino 6-xylidino 5-methylpyrimidyl-2 alpha-(alpha-phenyl carboxy-propyl) sulphide 4-methylamino fi-toluido pyrimidyl- 2 beta-(care boxy-ethyl) sulphide V Z-benzylamino G-phenethylamino pyrimidyl-4 alpha- (-alpha-phenyl" beta-tolyl--carboxy-ethyl)' sulphide V M 4-cyclopentylamino 6-Xylidino pyrimidyl-Z beta- (alpha, alpha-dibutyl beta-benzyl carboxypropyl) sulphide 7 4 methylamino 6- naphthylamino 5 methyl pyrimidyl-2 alpha-(carboxy-ethyl) sulphide l-anilino fi-methylamino pyrimid yle2 carboxymethyl sulphide 2-cyclopentylamino -6-phenethylamino 5-tolyl -pyrimidyl-4- carboxymethyl sulphide 4,6-diamino pyrimidy-L-Z beta- (alpha-cyclohexyl carboxy-butyl) sulphide 4-amino 6-allylamino pyrimidyI-Z 5-cyclohexenyl carboxy-methyl sulphide 4,6-di- (naphthylamino) I pyrimidyl-2 alpha-(carboxy-ethylysulphide 2-chlorotolylamino fi-amino' pyrimidy-ll beta (carboxy-ethyl) sulphide 4,6-diamino pyrimidyl-2 alpha- (carboxy-propyl) sulphide a 4,6-diamino pyrimidyl-Z icarbo xy- (chlorophenyl) methyl sulphide p i 2,6-diamino pyrimidy-l-4 beta-(carboxy-propyl) sulphide pyrimidy1-2 beta- (car- 4,6-diamino pyrimidyl-Z alpha-(carboxy-butyl) sulphide 2,6-diamino pyrimidyl-4' beta-(carboxy-butyl) and the ammonium and alkali-metal (e. g., so-- dium, potassium, etc.) salts of the above-mentioned sulphides.

In a manner similar to that described above with particular reference to the diamino [(--NI IR)2l'pyrimidy1 (or 1,3-diazinyl) carboxymethyl and carboxy-ethyl sulphides, corresponding derivatives of the 1,2-diazines and of the 1,4-diazines may be prepared. It also will be understood by those skilled in the art from the foregoing description of the preparation of a diazine monosulphide that similar compounds may be prepared in which two -or three sulphur atoms are attached directly to a carbon atom of the diazine nucleus and which have attached to each sulphur atom a (CnR2n)COOZ grouping, where n, R and Z have the meanings above given with reference to Formula I.

What we claim as new and desire to secure by Letters Patent of the United States is:

1. Chemical compounds corresponding; to the general formula where n is an integer and is at least 1 and not more than 2, R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals, and Z represents a member of the class consisting of hydrogen, the ammonium radical and alkali metals.

2. Chemical compounds as in claim 1 wherein R represents hydrogen.

3. Chemical compounds corresponding to the general formula where n is an integer and-is at least 1 and not more than 2, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

4. Chemical compounds as in claim 3 wherein R represents hydrogen.

5. Chemical compounds corresponding to the general formula where is an integer and is at least 1 and not more than 2, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

6. A diamino pyrimidyl carboxy-methyl sulphide.

7. 4,6-diamino pyrimidyl-2 carboxy-methyl sulphide.

8. A diamino pyrimidyl carboxy-ethyl sulphide.

9. 4,6-diamino pyrimidyl-2 alpha-(carboxyethyl) sulphide.

10. 4,6-diamino pyrimidyl-2 beta-(carboxyethyl) sulphide.

11. The method of preparing chemical compounds corresponding to the general formula where R has the meaning above given, and (2.) a compound corresponding to the general formula where X represents halogen, and n, R and Z have the meanings above given.

1-2. A method as in claim 11 wherein the hydrohalide acceptor is an alkali-metal hydroxide.

1s. The method which includes the step of treating with an inorganic acid a compound corresponding to the general formula where n is an integer and is at least 1 and not more than 2, R. represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals, and M represents a member of the class consisting of the ammonium radical and alkali metals, said acid being employed in an amount just sufiicient to convert the COOM grouping of the said compound to a -COOH grouping.

14. The method of preparing a diamino pyrimidyl carboxy-methyl sulphide which comprises effecting reaction, in the presence of a hydrohalide acceptor, between a mercapto diamino pyrimidine and an alkali-metal salt of chloroacetic acid thereby to obtain the alkali-metal salt of a diamino pyrimidyl carboxy-methyl sulphide, and treating the said alkali-metal salt withan inorganic acid in an amount just sufiicient to convert it to the corresponding diamino pyrimidyl carboxy-methyl sulphide.

15. A method as in claim 14 wherein the hydrohalide acceptor is an alkali-metal hydroxide.

16. The method of preparing 4,6-diamino pyrimidyl-Z carboxy-methyl sulphide which comprises effecting reaction, in the presence of sodium hydroxide, between 2-mercapto 4,6-diamino pyrimidine and sodium chloroacetate thereby to obtain the sodium salt of 4,6-diamino pyrimidyl-Z carboxy-methyl sulphide, and treating the said sodium salt with hydrochloric acid in an amount just suflicient to form 4,6-diamino pyrimidyl-2 carboxy-methyl sulphide.

GAETANO F. DALELIO. JAMES W. UNDERWOOD.

CERTIFICATE OF CORRECTION. Patent No 2, Lm992. May 2, 19m.

GAETANO F. D ALELIO, ET AL.

It is hereb; certified that error appears in the printed specification of the above numbered patent requiring correctionas follows Page 2, first column, line 26, for a salt or" read --a salt of-; page it, first column, line 58,for "pyrimidyl-2-" read pyrimidyl-Z and that the said Letters Patent shouldbe read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 25th day of July, A. D. 19bit.

Leslie Frazer 

